View source for Charcot–Marie–Tooth disease

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==Overview==
'''Charcot–Marie–Tooth disease''' ('''CMT'''), also known as '''Charcot–Marie–Tooth neuropathy''', '''hereditary motor and sensory neuropathy''' ('''HMSN''') and '''peroneal muscular atrophy''' ('''PMA'''), is a genetically and clinically heterogeneous group of inherited disorders of the [[peripheral nervous system]] characterised by progressive loss of [[muscle tissue]] and touch sensation across various parts of the body. Currently incurable, this disease is the most commonly inherited neurological disorder, and affects approximately 1 in 2,500 people<ref name="Krajewski"/><ref name="Medscape">[http://emedicine.medscape.com/article/315260-overview Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease]. Medscape. Retrieved March 20th, 2012.</ref> equating to approximately 26,000 people in the [[United Kingdom]] and 128,000 people in the United States. CMT was previously classified as a subtype of [[muscular dystrophy]].<ref name=Krajewski>{{cite journal |pages=1516–27 |doi=10.1093/brain/123.7.1516 |title=Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A |year=2000 |last1=Krajewski |first1=K. M. |journal=Brain |volume=123 |issue=7 |pmid=10869062}}</ref>

==Signs and symptoms==
Symptoms of CMT usually begin in early childhood or early adulthood, but can begin earlier. Some people do not experience symptoms until their early thirties or forties. Usually, the initial symptom is [[foot drop]] early in the course of the disease. This can also cause [[hammer toe]], where the toes are always curled. Wasting of muscle tissue of the lower parts of the legs may give rise to a "stork leg" or "inverted champagne bottle" appearance. Weakness in the hands and forearms occurs in many people as the disease progresses.

Loss of touch sensation in the feet, ankles and legs, as well as in the hands, wrists and arms occur with various types of the disease. Early and late onset forms occur with 'on and off' painful spasmodic muscular contractions that can be disabling when the disease activates.  High arched feet ([[pes cavus]]) or flat arched feet ([[pes planus]]) are classically associated with the disorder.<ref name="LeBhushan2014">{{cite book|last1=Le|first1=Tao|last2=Bhushan|first2=Vikas|title=First Aid for the USMLE Step 1 2014|url=http://books.google.com/books?id=3yJ-mgEACAAJ|accessdate=4 September 2014|date=6 January 2014|publisher=McGraw-Hill Education|isbn=9780071831420|quote=Typically autosomal dominant inheritance pattern associated with scoliosis and foot deformities (high or flat arches).}}</ref> Sensory and proprioceptive nerves in the hands and feet are often damaged, while pain nerves are left intact. Overuse of an affected hand or limb can activate symptoms including numbness, spasm, and painful cramping.

Symptoms and progression of the disease can vary. Involuntary grinding of teeth as well as squinting are prevalent and often go unnoticed by the person affected. Breathing can be affected in some; so can hearing, vision, as well as the neck and shoulder muscles. [[Scoliosis]] is common, causing hunching and loss of height. [[Acetabulum|Hip sockets]] can be malformed. Gastrointestinal problems can be part of CMT,<ref>http://www.lindacrabtree.com/cmt/basics/basics_article1.html{{full|date=December 2014}}</ref><ref>{{cite journal |author=Soykan I, McCallum RW |title=Gastrointestinal involvement in neurologic disorders: Stiff-man and Charcot-Marie-Tooth syndromes |journal=The American Journal of the Medical Sciences |volume=313 |issue=1 |pages=70–3 |date=January 1997 |pmid=9001170 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0002-9629&volume=313&issue=1&spage=70 |doi=10.1097/00000441-199701000-00012}}</ref> as can difficulty chewing, swallowing, and speaking (due to atrophy of [[vocal cords]]).<ref>http://www.ninds.nih.gov/disorders/charcot_marie_tooth/detail_charcot_marie_tooth.htm#265923092{{full|date=December 2014}}</ref> A [[tremor]] can develop as muscles waste. [[Pregnancy]] has been known to exacerbate CMT, as well as extreme emotional stress. Patients with CMT must avoid periods of prolonged immobility such as when recovering from a secondary injury as prolonged periods of limited mobility can drastically accelerate symptoms of CMT.<ref name=cmtausaTreat>{{cite press release |title=Treatment and Management of CMT |publisher=Charcot-Marie-Tooth Association |date=October 6, 2010 |url=http://www.cmtausa.org/index.php?option=com_content&view=article&id=74&catid=10&Itemid=51 |accessdate=August 26, 2011}}</ref>

[[Pain]] due to postural changes, skeletal deformations, muscular fatigue and cramping is fairly common in people with CMT. It can be mitigated or treated by physical therapies, surgeries, and corrective or assistive devices. [[Analgesic]] medications may also be needed if other therapies do not provide relief from pain.<ref>http://patient.info/doctor/charcot-marie-tooth-disease</ref> [[Neuropathic pain]] is often a symptom of CMT, though, like other symptoms of CMT, its presence and severity varies from case to case. For some people, pain can be significant to severe and interfere with daily life activities. However, pain is not experienced by all people with CMT. When neuropathic pain is present as a symptom of CMT, it is comparable to that seen in other [[peripheral neuropathies]], as well as [[Postherpetic neuralgia]] and [[Complex regional pain syndrome]], among other diseases.<ref name="Carter">{{cite journal |pages=1560–4 |doi=10.1016/S0003-9993(98)90421-X |title=Neuropathic pain in Charcot-Marie-tooth disease |year=1998 |journal=Archives of Physical Medicine and Rehabilitation |volume=79 |issue=12 |pmid=9862301 |first1=Gregory T. |last1=Carter |first2=Mark P. |last2=Jensen |first3=Bradley S. |last3=Galer |first4=George H. |last4=Kraft |first5=Linda D. |last5=Crabtree |first6=Ruth M. |last6=Beardsley |first7=Richard T. |last7=Abresch |first8=Thomas D. |last8=Bird}}</ref>

==Causes==
Charcot–Marie–Tooth disease is caused by mutations that cause defects in neuronal proteins. Nerve signals are conducted by an [[axon]] with a [[myelin]] sheath wrapped around it. Most mutations in CMT affect the myelin sheath, but some affect the axon.

The most common cause of CMT (70-80% of the cases) is the duplication of a large region on the short arm of [[chromosome 17]] that includes the gene [[PMP22]]. Some mutations affect the gene [[MFN2]], which codes for a mitochondrial protein. Cells contain separate sets of genes in their [[cell nucleus|nucleus]] and in their [[mitochondria]]. In nerve cells, the mitochondria travel down the long axons. In some forms of CMT, mutated [[MFN2]] causes the mitochondria to form large clusters, or clots, which are unable to travel down the axon towards the [[synapses]]. This prevents the synapses from functioning.<ref name="Baloh">{{cite journal |pages=422–30 |doi=10.1523/JNEUROSCI.4798-06.2007 |title=Altered Axonal Mitochondrial Transport in the Pathogenesis of Charcot-Marie-Tooth Disease from Mitofusin 2 Mutations |year=2007 |last1=Baloh |first1=R. H. |last2=Schmidt |first2=R. E. |last3=Pestronk |first3=A. |last4=Milbrandt |first4=J. |journal=Journal of Neuroscience |volume=27 |issue=2 |pmid=17215403}}</ref>

CMT is divided into the primary demyelinating neuropathies (CMT1, CMT3, and CMT4) and the primary axonal neuropathies (CMT2), with frequent overlap. Another cell involved in CMT is the [[Schwann cell]], which creates the myelin sheath, by wrapping its plasma membrane around the axon in a structure that is sometimes compared to a [[Swiss roll]].<ref name=Berger>{{cite journal |pages=1–15 |doi= 10.1007/s10048-002-0130-z |title=Molecular cell biology of Charcot-Marie-Tooth disease |year=2002 |last1=Berger |first1=Philipp |last2=Young |first2=Peter |last3=Suter |first3=Ueli |journal=Neurogenetics |volume=4 |pmid=12030326 |issue=1}}</ref>

Neurons, Schwann cells, and [[fibroblast]]s work together to create a functional nerve.<ref>[[Neuron]]</ref><ref>[[Schwann cell]]</ref> Schwann cells and neurons exchange molecular signals that regulate survival and differentiation. These signals are disrupted in CMT.<ref name=Berger/>

Demyelinating Schwann cells causes abnormal axon structure and function. They may cause axon degeneration, or they may simply cause axons to malfunction.<ref name=Krajewski/>

The myelin sheath allows nerve cells to conduct signals faster. When the ''myelin sheath'' is damaged, nerve signals are slower, and this can be measured by a common neurological test, [[electromyography]]. When the ''axon'' is damaged, on the other hand, this results in a reduced compound muscle [[action potential]] (CMAP).<ref>{{cite journal |last=Yiu |first=Eppie M. |last2=Burns |first2=Joshua |last3=Ryan |first3=Monique M. |last4=Ouvrier |first4=Robert A. |year=2008 |title=Neurophysiologic abnormalities in children with Charcot-Marie-Tooth disease type 1A |journal=Journal of the Peripheral Nervous System |volume=13 |issue=3 |pages=236–241 |doi=10.1111/j.1529-8027.2008.00182.x |pmid=18844790}}</ref>

==Diagnosis==
CMT can be diagnosed through symptoms, through measurement of the speed of nerve impulses ([[nerve conduction studies]]), through [[biopsy]] of the nerve, and through DNA testing. DNA testing can give a definitive diagnosis, but not all the [[genetic marker]]s for CMT are known.  CMT is first noticed when someone develops lower leg weakness, such as foot drop; or foot deformities, including hammertoes and high arches. But signs alone do not lead to diagnosis.  Patients must be referred to a physician specialising in neurology or rehabilitation medicine. To see signs of muscle weakness the neurologist will ask patients to walk on their heels or to move part of their leg against an opposing force.  In order to identify sensory loss the neurologist will test for deep tendon reflexes, such as the knee jerk, which are reduced or absent in CMT. The doctor will also ask about family history because CMT is hereditary.  The lack of family history does not rule out CMT, but it will allow the doctor to rule out other causes of neuropathy such as diabetes or exposure to certain chemicals or drugs.<ref>http://www.charcot-marie-tooth.org/about_cmt/diagnosis.php{{full|date=December 2014}}</ref>

In 2010, CMT was one of the first diseases where the genetic cause of a particular patient's disease was precisely determined by sequencing the whole genome of an affected individual.  This was done by the scientists employed by the Charcot Marie Tooth Association (CMTA)<ref name="NYT2010">{{cite news |url=http://www.nytimes.com/2010/03/11/health/research/11gene.html |title=Disease Cause Is Pinpointed With Genome |first=Nicholas |last=Wade |newspaper=New York Times |date=2010-03-10}}</ref><ref name="Lupski2010">{{cite journal |pages=1181–91 |doi=10.1056/NEJMoa0908094 |title=Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy |year=2010 |last1=Lupski |first1=James R. |last2=Reid |first2=Jeffrey G. |last3=Gonzaga-Jauregui |first3=Claudia |last4=Rio Deiros |first4=David |last5=Chen |first5=David C.Y. |last6=Nazareth |first6=Lynne |last7=Bainbridge |first7=Matthew |last8=Dinh |first8=Huyen |last9=Jing |first9=Chyn |last10=Wheeler |first10=David A. |last11=McGuire |first11=Amy L. |last12=Zhang |first12=Feng |last13=Stankiewicz |first13=Pawel |last14=Halperin |first14=John J. |last15=Yang |first15=Chengyong |last16=Gehman |first16=Curtis |last17=Guo |first17=Danwei |last18=Irikat |first18=Rola K. |last19=Tom |first19=Warren |last20=Fantin |first20=Nick J. |last21=Muzny |first21=Donna M. |last22=Gibbs |first22=Richard A. |journal=New England Journal of Medicine |volume=362 |issue=13 |pmid=20220177|display-authors=8 }}</ref> Two mutations were identified in a gene, SH3TC2, known to cause CMT.  Researchers then compared the affected patient's genome to the genomes of the patient's mother, father, and seven siblings with and without the disease. The mother and father each had one normal and one mutant copy of this gene, and had mild or no symptoms. The offspring that inherited two mutant genes presented fully with the disease. Sequencing the initial patient's whole genome cost $50,000, but researchers estimated that it would soon cost $5,000 and become common.

===Classification===
{{further|Charcot-Marie-Tooth classifications}}
CMT is a result of genetic [[mutation]]s in a number of [[gene]]s. Based on the affected gene, CMT can be categorized into types and subtypes.<ref name="Lupski2010" />

==Management==
Although there is no current standard treatment, the use of [[ascorbic acid]] (vitamin C) has been proposed, and has shown some benefit in animal models.<ref name="pmid15034573">{{cite journal |pages=396–401 |doi=10.1038/nm1023 |title=Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease |year=2004 |last1=Passage |first1=Edith |last2=Norreel |first2=Jean Chrétien |last3=Noack-Fraissignes |first3=Pauline |last4=Sanguedolce |first4=Véronique |last5=Pizant |first5=Josette |last6=Thirion |first6=Xavier |last7=Robaglia-Schlupp |first7=Andrée |last8=Pellissier |first8=Jean François |last9=Fontés |first9=Michel |journal=Nature Medicine |volume=10 |issue=4 |pmid=15034573}}</ref> A clinical trial to determine the effectiveness of high doses of ascorbic acid in treating humans with CMT type 1A has been conducted.<ref>{{cite web |url=http://www.mda.org/research/view_ctrial.aspx?id=186 |work=Clinical Trials |title=Neuromuscular Trial/Study |publisher=Muscular Dystrophy Association |date=2007-07-18 |accessdate=2008-05-28}}</ref> The results of the trial upon children have shown that a high dosage intake of ascorbic acid is safe [but] did not demonstrate effectiveness.<ref>{{cite journal |pages=537–44 |doi=10.1016/S1474-4422(09)70108-5 |title=Ascorbic acid for Charcot–Marie–Tooth disease type 1A in children: A randomised, double-blind, placebo-controlled, safety and efficacy trial |year=2009 |last1=Burns |first1=Joshua |last2=Ouvrier |first2=Robert A |last3=Yiu |first3=Eppie M |last4=Joseph |first4=Pathma D |last5=Kornberg |first5=Andrew J |last6=Fahey |first6=Michael C |last7=Ryan |first7=Monique M |journal=Lancet Neurology |volume=8 |issue=6 |pmid=19427269}}</ref>

Often the most important goal for patients with CMT is to maintain movement, muscle strength, and flexibility. Therefore, physical therapy and moderate activity are usually recommended, but overexertion should be avoided.  A physiotherapist should be involved in designing an exercise program that fits a patient’s personal strengths and flexibility. Orthoses (bracing) can also be used to correct problems caused by CMT. An orthotist may address gait abnormalities by prescribing the use of [[ankle-foot orthoses]] (AFOs). These orthoses help control foot drop and ankle instability and often provide a better sense of balance for patients.  Appropriate footwear is also very important for people with CMT, but they often have difficulty finding well-fitting shoes because of their high arched feet and hammer toes. Due to the lack of good sensory reception in the feet, CMT patients may also need to see a podiatrist for help in trimming nails or removing calluses that develop on the pads of the feet. A final decision a patient can make is to have surgery. Using a podiatrist or an orthopedic surgeon, patients can choose to stabilize their feet or correct progressive problems. These procedures include straightening and pinning the toes, lowering the arch, and sometimes, fusing the ankle joint to provide stability.<ref name=cmtausaTreat/> CMT patients must take extra care to avoid falling because fractures take longer to heal in someone with an underlying disease process. Additionally, the resulting inactivity may cause the CMT to worsen.<ref name=cmtausaTreat/>

The Charcot-Marie-Tooth Association classifies the [[chemotherapy]] drug [[vincristine]] as a "definite high risk" and states that "vincristine has been proven hazardous and should be avoided by all CMT patients, including those with no symptoms."<ref>[http://www.charcot-marie-tooth.org/med_alert.php CMT Association: Medical Alert]</ref>

There are also several corrective surgical procedures that can be done to improve physical condition.

== History ==

The disease is named after those who classically described it: [[Jean-Martin Charcot]] (1825–1893), his pupil [[Pierre Marie]] (1853–1940)  ({{cite journal |title=Sur une forme particulière d'atrophie musculaire progressive, souvent familiale débutant par les pieds et les jambes et atteignant plus tard les mains |journal=Revue médicale |volume=6 |pages=97–138 |year=1886 |location=Paris }}), and [[Howard Henry Tooth]] (1856–1925) ("The peroneal type of progressive muscular atrophy", dissertation, London, 1886.)

==Media==
There is a documentary titled "Bernadette" that follows a young woman battling the disease. It was made in 2012 and is currently sold online.<ref>{{IMDb title|2189318|Bernadette}}</ref>

==Famous people with CMT==
*[[Julie Newmar]]
*[[Todd MacCulloch]]
*[[Kaleem Khan]]
*[[Victor Bailey (musician)]]<ref>http://www.notreble.com/buzz/2015/11/01/victor-bailey-battling-muscular-dystrophy/</ref>

== See also ==
* [[Palmoplantar keratoderma and spastic paraplegia]]
* [[Hereditary motor and sensory neuropathies]]
* [[Hereditary motor neuropathies]]
* [[Low copy repeats]]

==References==
{{reflist|30em}}

==External links==
* {{DMOZ|Health/Conditions_and_Diseases/Neurological_Disorders/Peripheral_Nervous_System/Charcot-Marie-Tooth_Disease/}}

{{PNS diseases of the nervous system}}
{{Inherited disorders of trafficking}}
{{Cytoskeletal defects}}
{{Cell membrane protein disorders}}
{{Deficiencies of intracellular signaling peptides and proteins}}

{{DEFAULTSORT:Charcot-Marie-Tooth Disease}}
[[Category:Peripheral nervous system disorders]]
[[Category:Cytoskeletal defects]]
[[Category:Syndromes]]